CONCERTS - DYNAMIC CONNECTION OF FRAGMENTS AS AN APPROACH TO DE-NOVO LIGAND DESIGN

We have implemented and tested a new approach to de novo Ligand design , CONCERTS (creation of novel compounds by evaluation of residues at t arget sites). In this method, each member of a user-defined set of fra gments is allowed to move independently about a target active site dur ing a molecular dynamics simulation. This allows the fragments to samp le various low-energy orientations. When the geometry between proximal fragments is appropriate, bonds can be formed between the fragments. In this fashion, larger molecules can be built. The bonding arrangemen t can subsequently be changed-breaking bonds between chosen fragment p airs and forming them between other pairs-if the overall process creat es lower energy molecules. We have tested this method with various mix es of fragments against the active sites of the FK506 binding protein (FKBP-12) and HIV-1 aspartyl protease. In several cases, CONCERTS sugg ests ligands which are in surprisingly good agreement with known inhib itors of these proteins.